The present invention relates to substituted benzo(d)isoxazol-3-yl amine compounds, processes for their production, medicaments containing these compounds, as well as the use of these compounds for the production of medicaments.
The treatment of pain, in particular neuropathic pain, is extremely important in medicine. There is therefore a universal need for effective pain treatments. The urgent need for a patient-friendly and target-oriented treatment of chronic and non-chronic pain states, by which is understood the treatment of pain which is successful and satisfactory for the patient, is also documented in the large number of scientific articles and papers that have recently appeared in the field of applied analgesics and basic research in nociception.
A pathophysiological feature of chronic pain is the over-excitability of neurons. Neuronal excitability is decisively influenced by the activity of K+ channels, since these decisively determine the resting membrane potential of the cell and thus the excitability threshold. Heteromeric K+ channels from the molecular subtype KCNQ2/3 (Kv7.2/7.3) are expressed in neurons of various regions of the central nervous system (hippocampus, amygdala) and peripheral nervous system (posterior dorsal root ganglia) and regulate their excitability. The activation of KCNQ2/3 K+ channels leads to a hyperpolarisation of the cell membrane and, concomitantly, to a decrease in the electrical excitability of these neurons. KCNQ2/3-expressing neurons of the posterior dorsal root ganglia are involved in the transmission of nociceptive stimuli from the periphery to the spinal cord (Passmore et al., 2003). Accordingly, an analgesic effectiveness could be detected for the KCNQ2/3 agonist retigabin in preclinical neuropathic pain and inflammatory pain models (Blackburn-Munro and Jensen, 2003; Passmore et al., 2003; Dost et al., 2004). The KCNQ2/3 K+ channel is thus a suitable starting point for the treatment of pain, in particular pain selected from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., 2004), especially neuropathic and inflammatory pain. Moreover, the KCNQ2/3 K+ channel is a suitable target for the treatment of a large number of further medical conditions, such as for example migraine (US2002/0128277), cognitive disorders (Gribkoff, 2003), anxiety states (Korsgaard et al., 2005), epilepsy (Wickenden et al. 2004) and urinary incontinence (Streng et al. 2004).